BACKGROUND Klinefelter syndrome (KS) has been defined by sex chromosome aneuploidies (classically 47, XXY) in the male patient. The peripubertal timeframe in KS patients has been associated with the initiation of progressive testicular fibrosis, loss of spermatogonial stem cells (SSC), hypogonadism and impaired fertility. Less than half of KS patients are positive for spermatozoa in the ejaculate or testis via semen analysis or testicular sperm extraction, respectively. However, the chance of finding spermatogonia including a sub-population of SSCs in KS testes has not been well defined. Given the recent demonstration of successful cell culture for mouse and human SSCs, it could be feasible to isolate and propagate SSCs and transplant the cells back to the patient or to differentiate them in vitro to haploid cells. OBJECTIVE AND RATIONALE The main objective of this study was to meta-analyse the currently available data from KS patients to identify the prevalence of KS patients with spermatogonia on testicular biopsy across four age groups (year): fetal/infantile (age ≤ 1), prepubertal (age 1 ≤ x ≤ 10), peripubertal/adolescent (age 10 < x < 18) and adult (age ≥ 18) ages. Additionally, the association of endocrine parameters with presence or absence of spermatogonia was tested to obtain a more powered analysis of whether FSH, LH, testosterone and inhibin B can serve as predictive markers for successful spermatogonia retrieval. SEARCH METHODS A thorough Medline/PubMed search was conducted using the following search terms: 'Klinefelter, germ cells, spermatogenesis and spermatogonia', yielding results from 1 October 1965 to 3 February 2019. Relevant articles were added from the bibliographies of selected articles. Exclusion criteria included non-English language, abstracts only, non-human data and review papers. OUTCOMES A total of 751 papers were identified with independent review returning 36 papers with relevant information for meta-analysis on 386 patients. For the most part, articles were case reports, case-controlled series and cohort studies (level IV-VI evidence). Spermatogonial cells were present in all of the fetal/infantile and 83% of the prepubertal patients' testes, and in 42.7% and 48.5% of the peripubertal and adult groups, respectively were positive for spermatogonia. Additionally, 26 of the 56 (46.4%) peripubertal/adolescent and 37 of the 152 (24.3%) adult patients negative for spermatozoa were positive for spermatogonia (P < 0.05). In peripubertal/adolescent patients, the mean ± SEM level for FSH was 12.88 ± 3.13 IU/L for spermatogonia positive patients and 30.42 ± 4.05 IU/L for spermatogonia negative patients (P = 0.001); the mean ± SEM level LH levels were 4.36 ± 1.31 and 11.43 ± 1.68 IU/L for spermatogonia positive and negative, respectively (P < 0.01); the mean ± SEM level for testosterone levels were 5.04 ± 1.37 and 9.05 ± 0.94 nmol/L (equal to 145 ± 40 and 261 ± 27 and ng/dl) for the spermatogonia positive and negative groups, respectively (P < 0.05), while the difference in means for inhibin B was not statistically significant (P > 0.05). A similar analysis in the adult group showed the FSH levels in spermatogonia positive and negative patients to be 25.77 ± 2.78 and 36.12 ± 2.90 IU/L, respectively (mean ± SEM level, P < 0.05). All other hormone measurements were not statistically significantly different between groups. WIDER IMPLICATIONS While azoospermia is a common finding in the KS patient population, many patients are positive for spermatogonia. Recent advances in SSC in vitro propagation, transplantation and differentiation open new avenues for these patients for fertility preservation. This would offer a new subset of KS patients a chance of biological paternity. Data surrounding the hormonal profiles of KS patients and their relation to fertility should be interpreted with caution as a paucity of adequately powered data exists. Future work is needed to clarify the utility of FSH, LH, testosterone and inhibin B as biomarkers for successful retrieval of spermatogonia.

中文翻译：

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Klinefelter 综合征患者与年龄相关的精原细胞存在：系统评价和荟萃分析。

背景 Klinefelter 综合征 (KS) 已被定义为男性患者的性染色体非整倍体（经典 47，XXY）。KS 患者的青春期前后时间与进行性睾丸纤维化、精原干细胞 (SSC) 丧失、性腺功能减退和生育能力受损有关。分别通过精液分析或睾丸精子提取，不到一半的 KS 患者射精或睾丸中的精子呈阳性。然而，在 KS 睾丸中发现精原细胞（包括 SSC 亚群）的机会尚未明确。鉴于最近对小鼠和人类 SSC 细胞培养的成功证明，分离和繁殖 SSC 并将细胞移植回患者或在体外将它们分化为单倍体细胞是可行的。目的和基本原理 本研究的主要目的是对 KS 患者目前可用的数据进行荟萃分析，以确定 KS 患者在四个年龄组（年）的睾丸活检中的精原细胞患病率：胎儿/婴儿（年龄 ≤ 1），青春期前（年龄 1 ≤ x ≤ 10）、青春期前/青春期（年龄 10 < x < 18）和成人（年龄 ≥ 18）年龄。此外，对内分泌参数与精原细胞存在与否的关联进行了测试，以更有效地分析 FSH、LH、睾酮和抑制素 B 是否可以作为成功恢复精原细胞的预测标志物。搜索方法 使用以下搜索词进行了彻底的 Medline/PubMed 搜索：“Klinefelter、生殖细胞、精子发生和精原细胞”，结果从 1965 年 10 月 1 日到 2019 年 2 月 3 日。相关文章是从选定文章的参考书目中添加的。排除标准包括非英语语言、仅摘要、非人类数据和评论论文。结果 共确定了 751 篇论文，独立审查返回了 36 篇包含相关信息的论文，用于对 386 名患者进行荟萃分析。在大多数情况下，文章是病例报告、病例对照系列和队列研究（IV-VI 级证据）。精原细胞存在于所有胎儿/婴儿和 83% 的青春期前患者的睾丸中，并且在青春期前组和成人组中分别有 42.7% 和 48.5% 的精原细胞呈阳性。此外，56 名（46.4%）青春期/青少年中的 26 名（46.4%）和 152 名（24.3%）精子阴性的成年患者中的 37 名（P < 0.05）精原细胞阳性。在青春期/青春期患者中，精原细胞阳性患者 FSH 的平均值 ± SEM 水平为 12.88 ± 3.13 IU/L，精原细胞阴性患者为 30.42 ± 4.05 IU/L（P = 0.001）；精原细胞阳性和阴性的平均 ± SEM 水平 LH 水平分别为 4.36 ± 1.31 和 11.43 ± 1.68 IU/L（P < 0.01）；精原细胞阳性组和阴性组睾酮水平的平均值±SEM水平分别为5.04±1.37和9.05±0.94 nmol/L（等于145±40和261±27和ng/dl）（P <0.05），而抑制素 B 的平均值差异无统计学意义（P > 0.05）。成人组的类似分析显示，精原细胞阳性和阴性患者的 FSH 水平分别为 25.77 ± 2.78 和 36.12 ± 2.90 IU/L（平均值 ± SEM 水平，P < 0.05）。所有其他激素测量值在各组之间没有统计学上的显着差异。更广泛的影响 虽然无精子症在 KS 患者群体中很常见，但许多患者的精原细胞呈阳性。SSC 体外繁殖、移植和分化的最新进展为这些患者保留生育能力开辟了新途径。这将为新的 KS 患者子集提供生物学亲子关系的机会。由于缺乏足够有力的数据，应谨慎解释有关 KS 患者激素谱及其与生育能力的关系的数据。未来的工作需要阐明 FSH、LH、睾酮和抑制素 B 作为成功提取精原细胞的生物标志物的效用。更广泛的影响 虽然无精子症在 KS 患者群体中很常见，但许多患者的精原细胞呈阳性。SSC 体外繁殖、移植和分化的最新进展为这些患者保留生育能力开辟了新途径。这将为新的 KS 患者子集提供生物学亲子关系的机会。由于缺乏足够有力的数据，应谨慎解释有关 KS 患者激素谱及其与生育能力的关系的数据。未来的工作需要阐明 FSH、LH、睾酮和抑制素 B 作为成功提取精原细胞的生物标志物的效用。更广泛的影响 虽然无精子症在 KS 患者群体中很常见，但许多患者的精原细胞呈阳性。SSC 体外繁殖、移植和分化的最新进展为这些患者保留生育能力开辟了新途径。这将为新的 KS 患者子集提供生物学亲子关系的机会。由于缺乏足够有力的数据，应谨慎解释有关 KS 患者激素谱及其与生育能力的关系的数据。未来的工作需要阐明 FSH、LH、睾酮和抑制素 B 作为成功提取精原细胞的生物标志物的效用。移植和分化为这些患者保留生育能力开辟了新途径。这将为新的 KS 患者子集提供生物学亲子关系的机会。由于缺乏足够有力的数据，应谨慎解释有关 KS 患者激素谱及其与生育能力的关系的数据。未来的工作需要阐明 FSH、LH、睾酮和抑制素 B 作为成功提取精原细胞的生物标志物的效用。移植和分化为这些患者保留生育能力开辟了新途径。这将为新的 KS 患者子集提供生物学亲子关系的机会。由于缺乏足够有力的数据，应谨慎解释有关 KS 患者激素谱及其与生育能力的关系的数据。未来的工作需要阐明 FSH、LH、睾酮和抑制素 B 作为成功提取精原细胞的生物标志物的效用。